Silvestri Valentina, Valentini Virginia, Bucalo Agostino, Conti Giulia, Manzella Livia, Turchetti Daniela, Russo Antonio, Capalbo Carlo, Ottini Laura
Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.
Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy.
Cancers (Basel). 2024 Jan 27;16(3):548. doi: 10.3390/cancers16030548.
In the field of breast cancer care, a significant breakthrough has occurred with the recognition of HER2-low expression as a target for novel anti-HER2 antibody-drug conjugates (ADC). This discovery is reshaping the treatment landscape, challenging previous perceptions that considered HER2-low as clinically insignificant. The ability to target HER2-low expression is expected to have substantial clinical implications, irrespective of gender, including in cases of male breast cancer (MBC). However, an estimate of the prevalence of the HER2-low subtype in MBC is missing. This retrospective, observational, multicenter study was aimed at characterizing the HER2-low subtype in MBC. For the purpose of this study, the three-tiered categorization of HER2 (HER2-0, HER2-low, and HER2-positive) was used to reclassify the HER2-negative group into HER-0 or HER2-low subtypes. In the whole series of 144 invasive MBCs, 79 (54.9%) were HER2-0 (IHC scores of 0), 39 (27.1%) HER2-low (IHC scores of 1+/2+ with negative ISH), and 26 (18.0%) HER2-positive (IHC scores of 3+/2+ with positive ISH). Specifically, among hormone receptor-positive (HR+) HER2-negative invasive MBCs, 34.8% were HER2-low and 65.2% HER2-0. Compared with HER2-0, HER2-low subtype was associated with a positive lymph node involvement ( = 0.01). Other pathologic characteristics including histology, staging, and grading did not show notable variations between the two subtypes. The presence of germline pathogenic variants (PVs) did not significantly differ between HER2-0 and HER2-low MBCs. However, about 13% of HER2-low MBCs had germline PVs in genes, mainly , a clinically relevant observation in the context of combined target therapy. Overall, our data, which focused on the largest gender-specific breast cancer series, to our knowledge, confirm that the emerging three-tiered categorization of HER2 (HER2-0, HER2-low, and HER2-positive) can also be considered in MBC, to mitigate both the gender gap and the underrepresentation of males in clinical trials.
在乳腺癌治疗领域，随着HER2低表达被认定为新型抗HER2抗体药物偶联物（ADC）的靶点，出现了一项重大突破。这一发现正在重塑治疗格局，挑战了以往认为HER2低表达在临床上无足轻重的观念。无论性别如何，靶向HER2低表达的能力预计都将产生重大的临床意义，包括在男性乳腺癌（MBC）病例中。然而，目前尚缺乏对MBC中HER2低表达亚型患病率的估计。这项回顾性、观察性、多中心研究旨在对MBC中的HER2低表达亚型进行特征描述。为了本研究的目的，采用HER2的三级分类（HER2-0、HER2低表达和HER2阳性）将HER2阴性组重新分类为HER-0或HER2低表达亚型。在总共144例浸润性MBC中，79例（54.9%）为HER2-0（免疫组化评分为0），39例（27.1%）为HER2低表达（免疫组化评分为1+/2+且原位杂交阴性），26例（18.0%）为HER2阳性（免疫组化评分为3+/2+且原位杂交阳性）。具体而言，在激素受体阳性（HR+）HER2阴性浸润性MBC中，34.8%为HER2低表达，65.2%为HER2-0。与HER2-0相比，HER2低表达亚型与阳性淋巴结受累相关（P = 0.01）。包括组织学、分期和分级在内的其他病理特征在这两种亚型之间未显示出明显差异。HER2-0和HER2低表达MBC中胚系致病变异（PVs）的存在没有显著差异。然而，约13%的HER2低表达MBC在相关基因中有胚系PVs，主要是在联合靶向治疗背景下具有临床相关性的观察结果。总体而言，据我们所知，我们聚焦于最大的性别特异性乳腺癌系列的数据证实，在MBC中也可考虑采用新出现的HER2三级分类（HER2-0、HER2低表达和HER2阳性），以缩小性别差距并减少男性在临床试验中的代表性不足。
